Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
Cancer Sci. 2022 Jan;113(1):145-155. doi: 10.1111/cas.15183. Epub 2021 Nov 10.
To improve the poor survival rate of lung cancer patients, we investigated the role of HDGF-related protein 3 (HRP-3) as a potential biomarker for lung cancer. The expression of endogenous HRP-3 in human lung cancer tissues and xenograft tumor models is indicative of its clinical relevance in lung cancer. Additionally, we demonstrated that HRP-3 directly binds to the E2F1 promoter on chromatin. Interestingly, HRP-3 depletion in A549 cells impedes the binding of HRP-3 to the E2F1 promoter; this in turn hampers the interaction between Histone H3/H4 and HDAC1/2 on the E2F1 promoter, while concomitantly inducing Histone H3/H4 acetylation around the E2F1 promoter. The enhanced Histone H3/H4 acetylation on the E2F1 promoter through HRP-3 depletion increases the transcription level of E2F1. Furthermore, the increased E2F1 transcription levels lead to the enhanced transcription of Cyclin E, known as the E2F1-responsive gene, thus inducing S-phase accumulation. Therefore, our study provides evidence for the utility of HRP-3 as a biomarker for the prognosis and treatment of lung cancer. Furthermore, we delineated the capacity of HRP-3 to regulate the E2F1 transcription level via histone deacetylation.
为了提高肺癌患者的生存率，我们研究了 HRP-3 相关蛋白 3（HRP-3）作为肺癌潜在生物标志物的作用。内源性 HRP-3 在人肺癌组织和异种移植肿瘤模型中的表达表明其与肺癌的临床相关性。此外，我们证明 HRP-3 直接结合到染色质上的 E2F1 启动子上。有趣的是，A549 细胞中 HRP-3 的耗竭会阻碍 HRP-3 与 E2F1 启动子的结合；这反过来又阻碍了 E2F1 启动子上组蛋白 H3/H4 与 HDAC1/2 之间的相互作用，同时诱导 E2F1 启动子周围组蛋白 H3/H4 的乙酰化。通过 HRP-3 耗竭增加 E2F1 启动子上的组蛋白 H3/H4 乙酰化，从而增加 E2F1 的转录水平。此外，增加的 E2F1 转录水平导致 E2F1 反应基因 Cyclin E 的转录增强，从而诱导 S 期积累。因此，我们的研究为 HRP-3 作为肺癌预后和治疗的生物标志物提供了证据。此外，我们描绘了 HRP-3 通过组蛋白去乙酰化来调节 E2F1 转录水平的能力。
